Method of actuation of an alternating tangential flow diaphragm pump

ABSTRACT

A control unit includes a first connector configured to connect a proportional pressure regulator to a positive pressure supply and a second connector configured to connect the proportional pressure regulator to a negative pressure supply. The control unit further includes at least one sensor configured to detect an amount of air flow (volume per unit of time), positive or negative, within an air flow line connected to an output of the proportional pressure regulator, and a third connector configured to connect the air flow line to an air side of a diaphragm. Additionally, the control unit includes a controller programmed to control at least an opening and closing function of the proportional pressure regulator to attain a desired amount of air flow (volume per unit of time), positive or negative, within the air flow line.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of and priority to U.S. ProvisionalPatent Application No. 62/541,023, filed Aug. 3, 2017, the entiredisclosure of which is incorporated herein by reference in its entirety.

FIELD

The present application relates generally to actuation of diaphragmpumps, and more particularly, to methods, apparatuses and systems forthe same.

BACKGROUND

Diaphragm-operated pumps use positive and negative air flow to provideliquid transfer. However, conventional systems do not precisely controlthe change between positive and negative air flow or the amount ofpositive and negative air flow. Moreover, such systems often havecomplicated structures that are difficult to manufacture and maintain,and include air flow restrictions.

SUMMARY

The present application discloses a control unit comprising a firstconnector configured to connect a proportional pressure regulator to apositive pressure supply; a second connector configured to connect theproportional pressure regulator to a negative pressure supply; at leastone sensor configured to detect an amount of air flow (volume per unitof time), positive or negative, within an air flow line connected to anoutput of the proportional pressure regulator; a third connectorconfigured to connect the air flow line to an air side of a diaphragm;and a controller programmed to control at least an opening and closingfunction of the proportional pressure regulator to attain a desiredamount of air flow (volume per unit of time), positive or negative,within the air flow line.

The present application further discloses a method of actuating adiaphragm pump comprising selecting a volume or size of a diaphragmpump; selecting a volume of a fluid to be displaced by the diaphragmpump over a given period of time; selecting a duration of a pumpingoperation, which together with the desired volume of fluid to bedisplaced over said duration, generates a performance profileappropriate for a specific application; actuating the pumping operationby alternating a supply of positive and negative air flow in an air flowline connected at one end to an air side of the diaphragm pump andconnected at an opposite end to an output of an air flow regulator;monitoring an amount of air flow within the air flow line to maintain oralter a volume of air flowing per unit of time within the air flow line;optionally, monitoring a position of a diaphragm of the diaphragm pumpat one or both ends of its displacement; and optionally, altering thevolume of air flowing per unit of time within the air flow line toinfluence either the position of the diaphragm at one or both ends ofits displacement or a duration of a partial or full cycle ofdisplacement or both.

The present application still further discloses a method of controllinga diaphragm pump, comprising actuating a pumping operation of fluid froma first container by alternating a supply of positive and negative airflow to an air side of a diaphragm pump through an air flow lineconnected to an output of an air flow regulator; suctioning fluid fromthe first container by applying a supply of negative air flow to the airside of the diaphragm pump; regulating a duration of a partial or fullcycle of displacement of the diaphragm pump; filtering the fluidsuctioned from the first container; and extracting the filtered fluid soas to direct part of the filtered fluid back to the first container andto direct part of the filtered fluid to a second container.

The present application additionally discloses a method of controlling adiaphragm pump with a controller, comprising alternating betweensupplying a positive and negative air flow to an air side of a diaphragmpump to actuate pumping of a fluid associated with a bioreactor;suctioning fluid from the bioreactor by supplying a negative air flow tothe air side of the diaphragm pump; filtering the fluid suctioned fromthe bioreactor; extracting the filtered fluid to direct same to acontainer; and regulating a duration of a partial or full cycle ofdisplacement of the diaphragm pump, wherein the controller controlsdelivery of filtered fluid to the container in accordance with a processrequirement.

The disclosed embodiments may be modified and employed in various ways.For example, various configurations are readily apparent, including amultiplexed pumping system in which a plurality of pumps may becontrolled in a networked environment. Alternative exemplary embodimentsrelate to other features and combinations of features as may be recitedin the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The disclosure will become more fully understood from the followingdetailed description, taken in conjunction with the accompanyingfigures, wherein like reference numerals, symbols or terms generallyidentify similar components, unless context dictates otherwise, and inwhich:

FIG. 1 depicts a control system according to an exemplary embodiment.

FIG. 2 depicts the control system shown in FIG. 1 in which a side panelof a housing is removed to reveal one configuration of elements withinthe housing.

FIG. 3 depicts an alternating tangential flow control system accordingto an exemplary embodiment.

FIG. 4 depicts a control method according to an exemplary embodiment.

FIG. 5 depicts a schematic diagram according to an exemplary embodiment.

PREFERRED EMBODIMENTS

A preferred embodiment relates to a control unit, comprising a firstconnector configured to connect a proportional pressure regulator to apositive pressure supply; a second connector configured to connect theproportional pressure regulator to a negative pressure supply; at leastone sensor configured to detect an amount of air flow (volume per unitof time), positive or negative, within an air flow line connected to anoutput of the proportional pressure regulator; a third connectorconfigured to connect the air flow line to an air side of a diaphragm;and a controller programmed to control at least an opening and closingfunction of the proportional pressure regulator to attain a desiredamount air flow (volume per unit of time), positive or negative, withinthe air flow line.

Another preferred embodiment relates to a method of actuating adiaphragm pump comprising selecting a volume or size of the pump;selecting a volume of fluid to be displaced by the diaphragm pump over agiven period of time; selecting a duration of a pumping operation, whichtogether with the desired volume of fluid to be displaced over saidduration, generates a performance profile appropriate for a specificapplication; actuating the pumping operation by alternating a supply ofpositive and negative air flow in an air flow line connected at one endto an air side of the diaphragm pump and connected at an opposite end toan output of an air flow regulator; monitoring an amount of air flowwithin the air flow line to maintain or alter a volume of air flowingper unit of time within the air flow line; optionally, monitoring aposition of the diaphragm at both ends of its displacement; andoptionally, altering the volume of air flowing per unit of time withinthe air flow line to influence either the position of the diaphragm atone or both ends of its displacement or a duration of a partial or fullcycle of displacement or both.

Yet another preferred embodiment relates to a method of controlling adiaphragm pump, comprising actuating a pumping operation of fluid from afirst container by alternating a supply of positive and negative airflow to an air side of a diaphragm pump through an air flow lineconnected to an output of an air flow regulator; suctioning fluid fromthe first container by applying a supply of negative air flow to the airside of the diaphragm pump; regulating a duration of a partial or fullcycle of displacement of the diaphragm pump; filtering the fluidsuctioned from the first container; and extracting the filtered fluid soas to direct part of the fluid back to the first container and to directpart of the fluid to a second container.

A further preferred embodiment relates to a method of controlling adiaphragm pump with a controller, comprising alternating betweenapplying positive and negative air flow to an air side of a diaphragmpump to actuate pumping of a fluid associated with a bioreactor;suctioning fluid from the bioreactor by applying negative air flow tothe air side of the diaphragm pump; filtering the fluid suctioned fromthe bioreactor; extracting the filtered fluid to direct same to acontainer; and regulating a duration of partial or full cycle ofdisplacement of the diaphragm pump, wherein the controller controlsdelivery of filtered fluid to the container in accordance with a processrequirement.

DETAILED DESCRIPTION

Before turning to the figures, which illustrate the exemplaryembodiments in detail, it should be understood that the presentapplication is not limited to the details or methodology set forth inthe description or illustrated in the figures. It should also beunderstood that the terminology is for the purpose of description onlyand should not be regarded as limiting. The illustrative embodimentsdescribed in the detailed description, drawings, and claims are notmeant to be limiting. Other embodiments may be utilized, and otherchanges may be made, without departing from the spirit or scope of thesubject matter presented here. It will be readily understood that theaspects of the present disclosure, as generally described herein, andillustrated in the figures, can be arranged, substituted, combined, anddesigned in a wide variety of different configurations, all of which areexplicitly contemplated and made part of this disclosure.

Filtration of biological fluids may be performed to separate blood intoblood cells and plasma, among other implementations. For biomedicalapplications, it is important to be able to effectively clean thesystems used for such filtration, so as to achieve sterile orsubstantially sterile conditions and protect against contamination, inaccordance with Good Manufacturing Practice (GMP) guidelines. Forexample, alternating tangential flow systems include stainless steelcomponents which are sterilized by steaming or by gamma irradiation. Inparticular, “single use” components of alternating tangential flowsystems may be sterilized via gamma irradiation.

Alternating tangential flows of fluid may be used to perform filtering.More particularly, by alternating a tangential flow of fluid through afilter element, continuous filtration may be achieved. An alternatingtangential flow system is described, for example, in U.S. Pat. No.6,544,424 to Shevitz, the entire contents of which are incorporatedherein for the background, apparatuses and technical content therein.

Filtration may be performed for purification, selective removal ofunwanted constituents, and/or for maintaining a culture in perfusion ata high cell concentration. Various types of filters may be used,including hollow fiber filters containing a plurality of hollow fibersbundled together. Filtrating using the aforementioned alternatingtangential flow may be carried out, for example, by a diaphragm pump inwhich positive and negative air flows are delivered in an alternatingmanner for activating liquid transfer. Current systems do not preciselymodulate the duration of the transition between the positive andnegative air flows or the amount of air flow. Moreover, current systemstypically involve many components in complicated assemblies, which aredifficult to maintain. The embodiments of the present disclosure, on theother hand, allow for precise control over the duration of thetransition and amount, and allow for self-cleaning, among otherbenefits, as described in more detail below.

FIG. 1 depicts a system 100 according to an exemplary embodiment.Certain components of system 100 shown in FIG. 1 may be provided withina housing 7. However, it should be appreciated that in certainembodiments, the system 100 may include components outside of thehousing 7 which may be communicated, directly or indirectly, withcomponents inside the housing 7. The system 100 includes a firstconnector configured to connect a proportional pressure regulator 6,which is contained within the housing 7, to a positive pressure supply1. The proportional pressure regulator 6 may also be referred to as aproportional pressure valve. In at least one embodiment, theproportional pressure regulator 6 is a TR Pneumatic Pressure ControlSystem, Model TR-010-g10-s, made by Enfield® Technologies of Shelton,Conn., USA. The system further includes a second connector configured toconnect the proportional pressure regulator 6 to a negative pressuresupply 2. The positive pressure supply 1 and negative pressure supply 2are configured to provide, respectively, positive and negative air flow,as discussed in more detail below. The configuration of the positive andnegative air pressure supplies 1, 2 is such that the air flow to thediaphragm is not restricted, thus allowing operation under lowerincoming positive and negative pressures, thereby enhancing systemsafety. FIG. 2 depicts an exemplary representation of the system 100, inwhich a side panel of the housing is removed.

The system 100 includes at least one sensor 3 configured to detect anamount of air flow (volume per unit of time), positive or negative,within an air flow line 8 in the housing 7, and a third connectorconfigured to connect the housing to an air side of a diaphragm pump.More specifically, the air flow line 8 is provided in the housing and isarranged between the proportional pressure regulator 6 and the thirdconnector, such that the air flow line 8 is connected to an output ofthe proportional pressure regulator 6. The air flow line 8 imparts airflow that acts on the diaphragm pump. Further still, the system includesa controller (as may also be referred to as a control system, controlmodule or control unit) 5 which is programmed to control at least anopening and closing function of the proportional pressure regulator 6 toattain a desired amount of air flow (volume per unit of time), positiveor negative, within the air flow line 8.

Further, the controller 5 is programmed to regulate the flow of fluid ofa diaphragm pump by controlling the positive and negative air flowapplied via the third connector mentioned above. Accordingly, thecontroller 5 regulates operation of the diaphragm pump. Further, thecontroller 5 may adjust a flow of fluid from the diaphragm pump, inorder to satisfy a process requirement. For example, in response to asetting inputted by a user, the controller 5 may cause the diaphragmpump to output a specified volume of fluid within a predetermined timeperiod (e.g., 100 L in one day). An operator may provide an input to thecontroller 5 to specify a desired amount of outputted volume, and thecontroller 5 is programmed to control the diaphragm pump to achieve thedesired amount. For example, the controller 5 is programmed to determinea number of pumping cycles (e.g., a number of cycles per minute) toachieve a specified output in accordance with the user input. Further,the controller 5 is configured to adjust operation of the pump and thesupply of positive and negative air flow to account for variations. Forexample, over a time period such as one day, there may be changes influid viscosity over time, and the controller 5 is programmed toautomatically control the fluid flow to account for such changes, inorder to achieve the flow output specified by a user.

The controller may include a processor or microprocessor configured torun an operating system, an application-specific integrated circuit(ASIC), a field-programmable gate array (FPGA), etc., or combinationsthereof. The controller may include memory which may include, but is notlimited to, electronic, optical, magnetic, or any other storage ortransmission device capable of providing a processor, ASIC, FPGA, etc.with program instructions. The memory may include a memory chip,Electrically Erasable Programmable Read-Only Memory (EEPROM), erasableprogrammable read only memory (EPROM), flash memory, or any othersuitable memory from which the controller can read instructions. Theinstructions may include code from any suitable programming language.

Further, in certain embodiments, a user interface is provided whereusers of the control system 100 can input and/or monitor various facetsof the control system 100 and operation of associated pumps. Forexample, the user interface may be programmed to display one or moregraphical outputs of data received and analyzed by controller 5. Theuser interface may also display other data stored in the memory ofcontroller 5, including data relating to the duration and amount ofpositive and negative air flow supplied by the positive pressure supply1 and negative pressure supply 2, respectively, at each of a pluralityof process steps. Other information that may be shown on the userinterface includes data, showing minimum and maximum air flow amountsand volume, including tolerance ranges for air flow. Further still,additional parameters that may be displayed to the user at the userinterface include a flow rate and a cycle time for one or more processsteps.

Further still, the user interface of certain exemplary embodimentspermits the user to control starting or stopping of a control processcarried out by the controller 5. In some embodiments, starting andstopping functions may be controlled via buttons provided on atouch-screen display, for example. The user interface also allows forinput (entry) of specified control parameters. For example, a desiredamount of positive or negative pressure may be inputted by the user atthe user interface of controller 5. The desired amount of positive ornegative air flow is associated with a position of the diaphragm at bothends of its displacement when the diaphragm is connected to the housing7.

In particular, at the user interface, the user can instruct thecontroller 5 to apply a constant positive air flow to the firstconnector in housing 7, and to apply a constant negative air flow to thesecond connector, for example. The user may initially set a size (e.g.,in terms of volume) of the diaphragm pump to which the third connectoris connected. The controller 5 automatically resets a displacementvolume of the diaphragm based on the pump size. Next, the user may set avolume of a fluid to be displaced by the diaphragm pump over a givenperiod of time, where the flow rate is the product of the number of fullcycles per minute and the displacement volume per cycle. The controlleris further programmed to adjust a duration of a full cycle of thediaphragm's displacement over a single pumping cycle or a plurality ofpumping cycles, and to control displacement of a volume of fluid over apredetermined time period.

Additionally, either manually or in accordance with an algorithm ormathematical recipe, the user may further input the desired duration ofa pumping operation, which, together with the desired volume of fluid tobe displaced over said duration, generates a performance profileappropriate for a specific application, such as cell harvesting, may begenerated. The performance profile may be based at least in part on thedetermined duration of a partial or full cycle of displacement of onepump or a plurality of pumps. The sensor 3 monitors air flow for eachstep and allows for comparison of the actual detected air flow to apredetermined threshold (e.g., an air flow corresponding to an allowedpressure). Further, in at least one embodiment, control system 100allows for pumping fluid through the pump in a constant or variable flowin accordance with the performance profile. The performance profile isbased on the determined duration and intensity for the plurality ofprocess steps. For example, the performance profile may be generatedbased on selections of a duration of a pumping operation, includingpredetermined amounts of positive and negative air flow at a givenprocess step. The controller 5 also allows for the user to adjust adegree of opening and/or closing of the regulator 6 in accordance withthe duration of a partial or full cycle of displacement of the diaphragmpump, as may be carried out in accordance with the performance profile.Further still, the controller 5 allows for regulating a transition fromopening to closing of the proportional pressure regulator 6 inaccordance with the transition between the application of the supply ofpositive and negative air flow. Thus, the ‘changeover’ between positiveand negative air flow may be precisely controlled. In particular, thecontroller 5 is configured to adjust a duration of a partial or fullcycle of displacement of the diaphragm pump to satisfy a processrequirement. Thus, the delivery of filtered fluid to a container may becontrolled in accordance with the process requirement.

The control system 100 may also be configured to provide information tocontroller 5 from one or more sensors other than the sensor 3. Forexample, in at least one embodiment, the controller 5 is configured toreceive an indication from at least one proximity sensor. The proximitysensor is disposed in a vicinity of the diaphragm and configured todetect a position of the diaphragm at one or both ends of itsdisplacement (i.e., the displacement achieved at end positions of thediaphragm under positive and negative pressure). For example, thecontroller 5 is responsive to an output of a proximity sensor disposedin a vicinity of the diaphragm and configured to detect at least aposition of the diaphragm at an end of its displacement (a “bottom”displacement) at a transition from a negative air flow to a positive airflow, and/or a position of the diaphragm at an end of its displacement(a “top” displacement) at a transition from a positive air flow to anegative air flow. Thus, the proximity sensor provides information tothe controller 5 indicating a relative position of the diaphragm. Thecontroller 5 adjusts a rate of fluid flow responsive to detection of theposition by the proximity sensor. In particular, end positions of thediaphragm may be continuously monitored by the proximity sensor.

The diaphragm position must attain its maximal end positions so as toachieve a full displacement per cycle and to achieve full flow over agiven time period. When the controller 5 determines, based oninformation from the proximity sensor, that one or more end positions isnot met, the controller is configured to automatically adjust theopening of regulator 6 to increase the air flow, positive or negative.The controller 5 may cause the system 100 to emit an audible warningwhen a fault is detected by the controller, for example, when thediaphragm fails to attain the correct position for a given number ofcycles. By way of further example, the controller 5 may receiveinformation from a probe that is configured to detect a property offluid flowing in the system 100, such as a glucose probe designed toindicate a glucose content of the fluid.

Furthermore, the control system 100 may also be configured to provideinformation to controller 5 from one or more sensors other than thepressure or proximity sensor. For example, in at least one embodiment,the controller 5 is configured to receive an indication from at leastone liquid flow meter (a flow sensor) which is configured to detect anamount of fluid flow and/or diaphragm pump displacement. The flow isdirectly related to the diaphragm pump displacement controlled bypositive and negative air flow. An additional flow meter (a flow sensor)on a filtrate side informs the user of the volume of the final productat any given time.

Moreover, at least one embodiment allows for a cleaning function to becarried out. In particular, the controller 5 controls the pressuresupplies 1, 2 so as to deliver a burst of air pressure at a specifiedtime so as to clean a filter of the pump. The controller 5 is programmedto cause the pump to perform a periodic filter cleaning cycle so as toremove unwanted particulates or debris from the filter. The cleaningcycle may be initiated manually, e.g., by selecting a ‘clean cycle’option on the user interface, or automatically, e.g., when thecontroller determines based on data collection or a time interval sincethe last cleaning that the cleaning cycle should be performed. Further,the controller is programmed to cause the respective pressure supplies1, 2 to supply at least one of positive or negative air flow at a firstflow rate, and to clean the filter by delivering at least one burst ofair flow at a second flow rate that is greater than the first flow rate.For example, the filter can be cleaned by applying a negative air flowand then delivering at least one burst of positive air flow at a secondflow rate that is greater than the first flow rate. In at least oneembodiment, a burst of air flow may be provided at a second rate that isat least twice as much as the first flow rate, for example.Additionally, cleaning can be performed using the pump. For example, thecontroller 5 may control the pump to have a short increase in pumpingflow with a return to a lower constant flow rate, which may beneficiallyincrease the filter life expectancy. In particular, the pump advancesthe flow of the filtrate to a second container, and the pump can stop orrun in reverse to increase the back pressure, thereby creating abackflow, and generate a desired cleaning effect. Further, an efficientcleaning process may be carried out by utilizing both the air burst andpump flow control as described above in conjunction with each other.Further still, the controller 5 may control the timing of a burst offluid flow, in addition to stopping or running the pump in reverse, aspart of a cleaning process.

In addition, the controller 5 is programmed to controlling a timing ofair pressure delivery to achieve a predetermined amount of air flowdelivered to the air flow line in the housing 7. That is, in addition toa specified quantity and flow rate, the user may also input timinginformation (start, stop, duration) at the user interface. For example,the user may input a start and stop time to define a predetermined timeperiod, and then the controller may effectuate control of the pressuresupplies 1, 2 to output a continuous flow of air over a predeterminedtime period. In particular, the controller 5 regulates the air flow,positive or negative, so as to output an air flow at a first rate for afirst period of time and output an air flow at a second rate for asecond period of time, where the first period is shorter than the secondperiod, and the first rate is higher than the second rate, or viceversa.

As mentioned above, in at least one embodiment, the controller isconfigured to perform a control for an alternating tangential flow pump.However, in at least one embodiment, the controller is configured toactivate a tangential filtration flow in a continuous manner, ratherthan a reciprocating action. Further, in at least one embodiment, thecontroller is configured to cause an independent pump to operateaccording to an alternating tangential filtration flow function or atangential filtration flow function by activating and controlling theindependent pump. When the pump is operated according to the tangentialfiltration flow function, the controller performs an initiation processto cause the pump to begin the tangential filtration flow. Thereafter,the controller performs monitoring of the flow. In such embodiments, theproportional pressure regulator 6 is not actuated when the tangentialfiltration flow function is carried out.

Turning now to FIG. 3, the system 100 shown in FIG. 1 may be provided ina bioreactor control system, according to an exemplary embodiment. Thebioreactor control system of at least one embodiment is a multiplexedsystem, and may be included with a bioreactor having multiple pumpingmodules or one controller 5 services two or more bioreactors. Inparticular, in at least one embodiment, the housing 7 may house aplurality of pumping modules allowing for connection with multiplepumping modules. The controller 5 determines an operating speed of eachpump. Other components of the bioreactor control system include abioreactor, a scale, a hollow filter module and a platform for the same.

Further, the control system allows for a user to initiate a perfusionprocess. The perfusion process includes supplying media and supplingglucose when glucose is not present in the media, or not present in adesired quantity. The perfusion process further includes performing cellseparation, permeation harvesting, and cell bleeding. To maintain aconstant reactor volume, the aforementioned perfusion process steps mustbe coordinated. For example, media should be added at substantially thesame rate at which permeate flows out of the system. In addition, therate of media addition may be adjusted in accordance with the glucosecontent and the cell bleed rate, to ensure that the reactor has aconstant volume. Cell bleeding and/or the addition of glucose areperformed intermittently to maintain a desired cell density. Inaddition, cell separation itself is accomplished using an alternatingtangential flow. The alternating tangential flow is established by theaction of an oscillating diaphragm which passes the cell culture backand forth through hollow fiber membranes of a filter. The permeate pumpflow rate may be synchronized with the diaphragm action to achieve adesired flow of permeate.

FIG. 5 depicts a schematic diagram of a bioreactor control systemaccording to an exemplary embodiment. The bioreactor control systemincludes a plurality of pumps, including a media pump, a glucose pump, ableed pump, and a perfusion pump. A plurality of flow meters may be usedby one controller (e.g., controller 5).

As further shown in FIG. 5, a vessel containing fresh media is connectedto a media pump and at least one flow controller FC. A vessel containingglucose is connected to a glucose pump and another flow controller FC.The speed and timing of the flow of glucose may be controlled by theoperator. The fresh media vessel, the glucose vessel, and theirrespective pumps are fluidly connected to a bioreactor, shown in theform of a jacketed mixing vessel in FIG. 5. One or more regulators maybe used to control the flow direction of material to and from thebioreactor. Material flowing to or from the bioreactor may be weighed onusing a weight transducer or weight sensor WT, and the measured weightmay be transmitted to the controller or displayed visually on a scaleindicator separate from a controller. In addition, the bioreactor iscommunicated with an analyzer transmitter AT and a flow controller FCdownstream of the bioreactor. The analyzer transmitter AT and the flowcontroller FC downstream of the bioreactor are configured to beconnected to a bleed pump. The bleed pump is in turn configured todischarge waste to a bleed waste tank. A fluid passage connects thediaphragm regulator to the bioreactor, with a flow meter disposed in thefluid passage to measure fluid characteristics of fluid which flows outfrom the bioreactor.

The system further includes a positive air pressure supply (shown withsupply line B) and a negative air pressure supply (shown with supplyline C) that are connected to a regulator (corresponding to theproportional pressure regulator 6). For the sake of illustration, theregulator in FIG. 5 is shown outside of the enclosure. The regulator isconnected to the perfusion pump and to at least one flow meter (flowtransducer or flow sensor). For example, as shown in FIG. 5, a flowtransducer FT1 is provided in the vicinity of the bioreactor, while aflow transducer FT2 is provided in the vicinity of the perfusion pump.The perfusion pump is fluidly connected to a vessel containing harvestmedia. At least one flow controller (e.g., a controller such ascontroller 5) is configured to receive volume and speed settings whichmay be inputted by an operator, e.g., at a user interface. Pressuretransducers (pressure sensors) PT1, PT2, PT3A may be disposed torespectively measure the pressure between the bioreactor and the filter,between the filter and the regulator, and between the filter and theperfusion pump, for example. Further, at least one flow controller isconfigured to receive, as an input, a desired shear rate for fluid flowwithin the system, which may be inputted at the user interface. Furtherstill, the flow controller is configured to receive, as an input, avessel value per day. The vessel value per day is a filtered volumeamount which generally corresponds to the volume of the vessel. Thecontroller 5 is also configured to receive parameters such as a valuablecell density as an input.

Such embodiments may be practiced in a networked environment usinglogical connections to one or more remote computers having processors.Persons skilled in the art will appreciate that such network computingenvironments may encompass many types of computers, including personalcomputers, hand-held devices, multi-processor systems,microprocessor-based or programmable consumer electronics, network PCs,minicomputers, mainframe computers, and so on. Implementations may alsobe practiced in distributed computing environments where tasks areperformed by local and remote processing devices that are linked (eitherby hardwired links, wireless links, or by a combination of hardwired orwireless links) through a communications network. In a distributedcomputing environment, program modules may be located in both local andremote memory storage devices.

The bioreactor control system also includes at least one communicationsunit that may be coupled to a switch and a router for providing acommunication link between the system and a network. As such, thecommunications unit enables the processor to communicate, wired orwirelessly, with other electronic systems coupled to the network. Forinstance, the communications unit may be coupled to an Ethernet linethat connects the system to the Internet or another network. In otherimplementations, the communications unit may be coupled to an antenna(not shown) and provides functionality to transmit and receiveinformation over a wireless communication interface with the network.

In various implementations, the communications unit may include one ormore transceivers configured to perform data communications inaccordance with one or more communications protocols including but notlimited to WLAN protocols (e.g., IEEE 802.11 a/b/g/n/ac/ad, IEEE 802.16,IEEE 802.20, etc.). Accordingly, the bioreactor control system allowsfor monitoring and control of pumping operations throughout thenetworked environment. Data collection and analysis for multiple pumpingmodules may also be carried out. Further, information such as a sensedpressure level from a diaphragm pressure sensor which is built in orattached to a diaphragm housing may be transmitted to controller 5.Sensed data indicative of an amount of fluid flow at a housing holdingthe diaphragm pump may also be obtained and provided to the controller.

By way of further example, the controller 5 may be connected, via thenetwork, to another controller, such as an independent controller of abioreactor vessel. Furthermore, in at least one embodiment, thecontroller 5 may be in communication with a suite of sensors whichmonitor operating temperature, fluid level, and rheological propertiesof the fluid. For example, an optical turbidity monitor can be providedwhich sends turbidity data to the controller 5, for example. Inaddition, information about the composition of the biological fluid mayalso be relayed to the controller 5 and conveyed to the user via theuser interface. For example, the density of cells in the biologicalfluid may be determined and displayed to the user. Additionally, dataanalysis may be performed so as to determine a performance profile basedon data from a plurality of pumps of the pumping system of thebioreactor control system. Further, statistical distributions ofinterest may be generated based on data from a plurality of pumps, andmay be used to assess pump system performance.

Further still, the bioreactor control system includes a plurality ofcontainers (vessels). For example, in at least one embodiment, thecontrol system contains a first vessel in which unfiltered material isstored, and a second vessel in which filtered material is stored. Thematerial may be a biological fluid, such as a fluid containing animal,human or microbial cells. The pump is activated so as to pump part ofthe fluid from the first vessel through a filter, and to deliver thefiltered fluid to the second vessel. More specifically, by applyingnegative air flow to the air flow line 8 in the housing 7, fluid may besuctioned from the first vessel. The delivery of fluid from the firstvessel to the diaphragm pump or another vessel may be controlled inaccordance with alternating the supply of positive and negative air flowamounts. Expulsion of fluid from the pump or vessel can be controlled inthe same manner as delivery of the fluid. Accordingly, in at least oneembodiment, biological fluid is suctioned from a bioreactor to a vessel,and a portion of the fluid may be returned to the bioreactor, whileanother portion may be directed to a vessel (e.g., a second container).In some embodiments, the second container may be refrigerated. Forexample, the filter (e.g., a hollow fiber filter) may be used toseparate biological fluid and direct part of the filtrates to the secondvessel. The alternating tangential flow may be used to continuouslyfilter the fluid until it reaches the second vessel.

Additionally, the pump can be operated to pump part of the fluid fromthe first vessel back to the first vessel (a return flow). Further, thecontroller 5 is operable to permit or restrict the flow of fluid fromthe second container, to permit or restrict the backflow (return flow)of fluid from the second container to the first container. Thecontroller 5 may restrict a backflow when a backflow function not usedto clean the filter (i.e., when the control system does not employ thebackflow function temporarily, in a cleaning state).

FIG. 4 depicts a control process 400 according to an embodiment. Theprocess 400 relates to an actuation operation of a pump which isequipped with a diaphragm. The process includes selecting a volume orsize of the pump (step 401) and selecting a flow rate (volume perminute) (step 402). The process further includes selecting a duration ofa pumping operation, including predetermined amounts of positive andnegative air flow at a given process step, to generate a performanceprofile appropriate for a specific application (step 403). Additionally,the process includes actuating the pumping operation by alternating asupply of positive and negative air flow through a regulator housedwithin a housing (step 404). Further, the process includes monitoring anamount of positive or negative air flow within the air flow line in thehousing to maintain or alter a volume of air flowing per unit of timewithin the air flow line (step 405). Optionally, additional processstep(s) may be carried out. For example, the control process 400 furtherincludes optionally monitoring a position of the diaphragm at one orboth ends of its displacement (step 406) and optionally altering thevolume of air flowing per unit of time within the air flow line toinfluence either the position of the diaphragm at one or both ends ofits displacement or a duration of a partial or full cycle ofdisplacement or both (step 407).

While this specification contains specific implementation details, theseshould not be construed as limitations on the scope of what may beclaimed, but rather as descriptions of features specific to particularimplementations. Certain features described in this specification in thecontext of separate implementations can also be implemented incombination in a single implementation. Conversely, various featuresdescribed in the context of a single implementation can also beimplemented in multiple implementations separately or in any suitablesubcombination. Moreover, although features may be described above asacting in certain combinations and even initially claimed as such, oneor more features from a claimed combination can in some cases be excisedfrom the combination, and the claimed combination may be directed to asubcombination or variation of a subcombination.

Similarly, while operations are depicted in the drawings in a particularorder, this should not be understood as requiring that such operationsbe performed in the particular order shown or in sequential order, orthat all illustrated operations be performed, to achieve desirableresults. In certain circumstances, the separation of various systemcomponents in the implementations described above should not beunderstood as requiring such separation in all implementations, and itshould be understood that the described components and systems cangenerally be integrated in a single product or packaged into multipleproducts.

As utilized herein, the terms “substantially” and similar terms areintended to have a broad meaning in harmony with the common and acceptedusage by those of ordinary skill in the art to which the subject matterof this disclosure pertains. It should be understood by those of skillin the art who review this disclosure that these terms are intended toallow a description of certain features described and claimed withoutrestricting the scope of these features to the precise numerical rangesprovided. Accordingly, these terms should be interpreted as indicatingthat insubstantial or inconsequential modifications or alterations ofthe subject matter described and claimed are considered to be within thescope of the invention as recited in the appended claims.

The terms “coupled,” “connected,” and the like as used herein mean thejoining of two components directly or indirectly to one another. Suchjoining may be stationary (e.g., permanent) or moveable (e.g., removableor releasable). Such joining may be achieved with the two components orthe two components and any additional intermediate components beingintegrally formed as a single unitary body with one another or with thetwo components or the two components and any additional intermediatecomponents being attached to one another.

The terms “fluidly coupled,” “in fluid communication,” and the like asused herein mean the two components or objects have a pathway formedbetween the two components or objects in which a fluid, such as water,air, biological fluid, etc., may flow, either with or withoutintervening components or objects. Examples of fluid couplings orconfigurations for enabling fluid communication may include piping,channels, or any other suitable components for enabling the flow of afluid from one component or object to another.

It is important to note that the construction and arrangement of thesystem shown in the various exemplary implementations is illustrativeonly and not restrictive in character. All changes and modificationsthat come within the spirit and/or scope of the describedimplementations are desired to be protected. It should be understoodthat some features may not be necessary and implementations lacking thevarious features may be contemplated as within the scope of theapplication, the scope being defined by the claims that follow. Inreading the claims, it is intended that when words such as “a,” “an,”“at least one,” or “at least one portion” are used there is no intentionto limit the claim to only one item unless specifically stated to thecontrary in the claim. When the language “at least a portion” and/or “aportion” is used the item can include a portion and/or the entire itemunless specifically stated to the contrary.

1. A control unit, comprising: a first connector configured to connect aproportional pressure regulator to a positive pressure supply; a secondconnector configured to connect the proportional pressure regulator to anegative pressure supply; at least one sensor configured to detect anamount of air flow (volume per unit of time), positive or negative,within an air flow line connected to an output of the proportionalpressure regulator; a third connector configured to connect the air flowline to an air side of a diaphragm; and a controller programmed tocontrol at least an opening and closing function of the proportionalpressure regulator to attain a desired amount of air flow (volume perunit of time), positive or negative, within the air flow line.
 2. Thecontrol unit of claim 1, which is contained in a housing.
 3. The controlunit of claim 1, in which the controller is further programmed to adjusta duration of a full cycle of the diaphragm's displacement over a singlepumping cycle or a plurality of pumping cycles.
 4. The control unit ofclaim 1, in which the controller is responsive to an output of at leastone proximity sensor disposed in a vicinity of the diaphragm andconfigured to detect at least a position of the diaphragm at an end ofits displacement (a “bottom” displacement) at a transition from anegative air flow to a positive air flow.
 5. The control unit of claim4, in which a position of the diaphragm at an end of its displacement (a“top” displacement) at a transition from a positive air flow to anegative air flow is also detected.
 6. The control unit of claim 1, inwhich the controller is responsive to outputs of two fluid flow sensorsconfigured to detect an amount of fluid flow and diaphragm pumpdisplacement.
 7. The control unit of claim 1, in which the diaphragm isassociated with an alternating tangential flow (ATF) pump.
 8. A methodof actuating a diaphragm pump comprising: selecting a volume or size ofa diaphragm pump; selecting a volume of a fluid to be displaced by thediaphragm pump over a given period of time; selecting a duration of apumping operation, which together with the desired volume of fluid to bedisplaced over said duration, generates a performance profileappropriate for a specific application; actuating the pumping operationby alternating a supply of positive and negative air flow in an air flowline connected at one end to an air side of the diaphragm pump andconnected at an opposite end to an output of an air flow regulator;monitoring an amount of air flow within the air flow line to maintain oralter a volume of air flowing per unit of time within the air flow line;optionally, monitoring a position of a diaphragm of the diaphragm pumpat one or both ends of its displacement; and optionally, altering thevolume of air flowing per unit of time within the air flow line toinfluence either the position of the diaphragm at one or both ends ofits displacement or a duration of a partial or full cycle ofdisplacement or both.
 9. The method of claim 8, further comprisingdelivering a burst of air pressure at a specified time so as to clean afilter of the pump.
 10. The method of claim 8, further comprisingpumping fluid through the pump in a constant or variable fluid flow inaccordance with the performance profile.
 11. The method of claim 8,further comprising: controlling a plurality of pumps communicated withina pumping system, wherein the performance profile is based at least inpart on the determined duration of a partial or full cycle ofdisplacement of each of the plurality of pumps.
 12. The method of claim8, wherein the diaphragm pump is communicated with an independent vesselcontroller.
 13. The method of claim 8, further comprising regulating adegree of opening and/or closing of the regulator in accordance with aduration of a partial or full cycle of displacement of the diaphragmpump.
 14. The method of claim 8, further comprising cleaning the pump byperforming a periodic filter cleaning cycle executed by a processor of acontroller in communication with the pump.
 15. A method of controlling adiaphragm pump, comprising: actuating a pumping operation of fluid froma first container by alternating a supply of a positive air flow and anegative air flow to an air side of a diaphragm pump through an air flowline connected to an output of an air flow regulator; suctioning fluidfrom the first container by applying a supply of negative air flow tothe air side of the diaphragm pump; monitoring a position of thediaphragm at one or both ends of its displacement; monitoring, by atleast one sensor, an amount of air flow within the air flow line;regulating in response to the monitored position of the diaphragm or theamount of air flow within the air flow line, a duration of a partial orfull cycle of displacement of the diaphragm pump; and filtering thefluid suctioned from the first container, thereby directing part of thefiltered fluid back to the first container and to direct a filtrate to asecond container.
 16. The method of claim 15, further comprising:regulating a transition from opening to closing of the regulator inaccordance with a transition between an application of the supply ofpositive and negative air flow.
 17. (canceled)
 18. The method of claim15, further comprising cleaning the filter by controlling the timing ofa burst of increased fluid flow from the fluid side of the diaphragmpump to clean the filter.
 19. The method of claim 15, further comprisingcontrolling a timing of delivery of an amount of air flow to the airflow line.
 20. The method of claim 15, further comprising: detecting,via at least one sensor in a vicinity of the diaphragm, a position of aportion of the diaphragm at both ends of its displacement.
 21. Themethod of claim 15, further comprising displacing a volume of fluid overa predetermined time period.
 22. The method of claim 15, furthercomprising adjusting a duration of a partial or full cycle ofdisplacement of the diaphragm pump to satisfy a process requirement. 23.A method of controlling a diaphragm pump with a controller, comprising:alternating between supplying a positive air flow and a negative airflow to an air side of a diaphragm pump to actuate pumping of a fluidassociated with a bioreactor; suctioning fluid from the bioreactor bysupplying a negative air flow to the air side of the diaphragm pump;filtering the fluid suctioned from the bioreactor through a filter;extracting the filtered fluid to direct same to a container; monitoring,by at least one sensor, a pressure level or an amount of a fluid flow ata housing holding the diaphragm pump; and regulating in response to themonitored the pressure level or the amount of the fluid flow at thehousing, a duration of a partial or full cycle of displacement of thediaphragm pump; wherein the controller controls delivery of filteredfluid to the container in accordance with a process requirement.
 24. Themethod of claim 23, wherein a portion of the filtered fluid is directedto a first flow area and another portion of the filtered fluid isdirected to a flow area other than the first flow area.
 25. (canceled)26. The method of claim 23, further comprising selecting a duration of apumping operation, including predetermined amounts of positive andnegative air flow at a given process step, to generate a performanceprofile appropriate for a specific application.
 27. The method of claim23, wherein the fluid comprises a biological fluid.
 28. The method ofclaim 23, wherein the controller is configured to monitor turbidity ofthe fluid.
 29. The method of claim 27, wherein the biological fluid is afluid containing animal, human, or microbial cells.
 30. The method ofclaim 23, wherein the controller is configured to control the pumpingfunction of a plurality of pumps connected in a pumping system.